Nicotine is the primary addictive component of tobacco products, which are responsible for millions of deaths worldwide each year. Addiction to nicotine appears to be unbalanced with greater vulnerability to the addictive properties in adolescents and females. These same vulnerabilities are found in rat models of nicotine use, therefore making this model an excellent tool for studying nicotine prevention and intervention therapies. The overall goal of this proposal is to examine the validity of using the novel therapy of exercise for nicotine prevention and intervention and specifically its effects on adolescent-onset nicotine use in male and female rats. Due to ongoing neurodevelopment the use of pharmacological therapies for treating addiction is controversial in human adolescents. Thus, exercise is an attractive alternative non-pharmacological therapy for nicotine addiction. The use of exercise for the prevention of nicotine dependence has not been explored to date. However, it's utility in cocaine addiction suggests exercise is a promising preventive strategy for nicotine as well. Preliminary studies suggest that exercise attenuates nicotine seeking behavior in adolescent-onset males. This finding supports the hypothesis that exercise is an effective nicotine use intervention. In specific aim one, behavioral experiments will assess exercise as a preventative therapy by focusing on its ability to slow rates of initiation to nicotine use, or acquisition. For the second specific aim, behavioral experiments will be used to examine the effect of exercise during abstinence on subsequent cue-induced nicotine-seeking. This is a clinically relevant model of craving because environmental cues are often important factors precipitating relapse in humans. In the third aim of the proposal, the molecular underpinnings of exercise's mechanism will be investigated. Since nicotine addiction is due to changes in neuroplasticity, specifically an increase in plasticity over time, intracellular signaling molecule known to be involved in nicotine self-administration and seeking as well as synaptic plasticity will be assessed. To compliment these data we will also perform electron microscopy to visualize structural plasticity at the level of the synapse. The overall hypothesis is that exercis will be an effective treatment for nicotine use prevention and intervention in adolescent-onset rats and will be particularly effective in female rats. Furthermore, the effects of exercise are hypothesized to be the result of blocking neuroadaptations, such as signaling and structural plasticity, associated with initiation and relapse. Findings from the proposed studies will contribute to the understanding of nicotine use vulnerability and mechanisms of exercise therapy as well as aiding in the development of targeted prevention/ intervention strategies for nicotine use in humans.